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Background: Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI)., Objectives: This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management., Methods: This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3-5., Results: The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month., Conclusions: In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800)., Competing Interests: Author Relationship With Industry Dr. Neumann has received lecture fees, paid to his institution, from Amgen, Daiichi-Sankyo, Novartis, and Ferrer; has received lecture fees, paid to his institution, and consulting fees, paid to his institution, from AstraZeneca and Boehringer Ingelheim; has received grant support and lecture fees, paid to his institution, from Pfizer, Biotronic, Edwards Lifesciences, Bayer HealthCare, and GlaxoSmithKline; and has received grant support from Medtronic, Abbott Vascular, and Boston Scientific. Dr. Sibbing has received personal fees from Bayer AG, Sanofi, AstraZeneca, Pfizer, Ferrer, and Daiichi-Sankyo; and has received grants and personal fees from Roche Diagnostics. Dr. Angiolillo has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payments for participation in review activities from CeloNova and St. Jude Medical; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr. Liebetrau has received consulting fees or honoraria from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, and Thermo Fisher; and has received research grants from Deutsche Herzstiftung, Kerckhoff-Stiftung, and Kühl-Stiftung outside the submitted work. Dr. Liebetrau’s institution has received payments for participation in clinical study programs from Abbott, AstraZeneca, Bayer, Biosensors, Boston Scientific, Daiichi-Sankyo, and Neovasc. Dr. Hamm has received Advisory Board and speaker fees from AstraZeneca and Daiichi-Sankyo. Dr. Sager has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (STRATO), the Else-Kröner-Fresenius-Stiftung, the Deutsche Herzstiftung, and the Deutsche Forschungsgemeinschaft. Dr. Joner has received personal fees from Biotronik, Orbus Neich, Boston Scientific, Edwards, AstraZeneca, and Recor; and has received grants from Boston Scientific, Edwards, and Amgen. Dr. Trenk has received consulting fees or honoraria from Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Ferrer, Pfizer, and Sanofi; and has received research grants from Deutsche Herzstiftung and PharmCompNet Baden-Wuerttemberg: Kompetenznetzwerk Pharmakologie Baden-Wuerttemberg outside the submitted work. Dr. Trenk’s institution has received payments for participation in clinical study programs from Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Doasense, Esperion, Idorsia, and Otsuka. Dr. Schunkert has received personal fees from Merck Sharp & Dohme, Amgen, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Servier, Brahms, Bristol Myers Squibb, Medtronic, Sanofi, Synlab, Pfizer, and Vifor; and has received grants and personal fees from AstraZeneca. Dr. Schüpke has received grants from the DZHK (German Center for Cardiovascular Research) and the Else Kröner-Fresenius-Stiftung; has received consulting fees from Bayer Vital GmbH; and has received lecture fees from Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Background: Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic strategy is to stimulate endogenous mechanisms of myocardial regeneration., Objectives: This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI., Methods: AnxA1 knockout (AnxA1 -/- ) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1., Results: AnxA1 -/- mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1 -/- mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx 3 cr1cre ERT2 Vegf flox/flox or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus., Conclusions: AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to test whether silencing of the transcription factor interferon regulatory factor 5 (IRF5) in cardiac macrophages improves infarct healing and attenuates post-myocardial infarction (MI) remodeling., Background: In healing wounds, the M1 toward M2 macrophage phenotype transition supports resolution of inflammation and tissue repair. Persistence of inflammatory M1 macrophages may derail healing and compromise organ functions. The transcription factor IRF5 up-regulates genes associated with M1 macrophages., Methods: Here we used nanoparticle-delivered small interfering ribonucleic acid (siRNA) to silence IRF5 in macrophages residing in MIs and in surgically-induced skin wounds in mice., Results: Infarct macrophages expressed high levels of IRF5 during the early inflammatory wound-healing stages (day 4 after coronary ligation), whereas expression of the transcription factor decreased during the resolution of inflammation (day 8). Following in vitro screening, we identified an siRNA sequence that, when delivered by nanoparticles to wound macrophages, efficiently suppressed expression of IRF5 in vivo. Reduction of IRF5 expression, a factor that regulates macrophage polarization, reduced expression of inflammatory M1 macrophage markers, supported resolution of inflammation, accelerated cutaneous and infarct healing, and attenuated development of post-MI heart failure after coronary ligation as measured by protease targeted fluorescence molecular tomography-computed tomography imaging and cardiac magnetic resonance imaging (p < 0.05)., Conclusions: This work identified a new therapeutic avenue to augment resolution of inflammation in healing infarcts by macrophage phenotype manipulation. This therapeutic concept may be used to attenuate post-MI remodeling and heart failure., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)